Dental Caries, Race and Incident Ischemic Stroke, Coronary Heart Disease, and Death.

BACKGROUND: Dental caries is a highly prevalent disease worldwide. In the United States, untreated dental caries is present in >1 in 5 adults. The objective of this study was to determine the relationship between dental caries and incident ischemic stroke, coronary heart disease (CHD) events, and death. METHODS: The dental cohort (n=6351) of the ARIC study (Atherosclerosis Risk in Communities) was followed for incident ischemic stroke, CHD event, and all-cause mortality. Of all the participants at visit 4 (n=11 656), those who were unable to go through dental examination, or with prevalent ischemic stroke and CHD events, were excluded. The full-mouth dental examination was conducted at visit 4 (1996-1998), assessing dental caries. The dose response of decayed, missing, and filled surfaces due to caries was assessed and related to the outcome. Outcomes were assessed through the end of 2019. Additionally, the effect of regular dental care utilization on dental caries was evaluated. RESULTS: Participants with ≥1 dental caries had an increased risk of stroke (adjusted hazard ratio [HR], 1.40 [95% CI, 1.10-1.79]) and death (adjusted HR, 1.13 [95% CI, 1.01-1.26]) but not for CHD events (adjusted HR, 1.13 [95% CI, 0.93-1.37]). The association of dental caries and ischemic incident stroke was significantly higher in the African American population compared with the White subgroup (interaction term P=0.0001). Increasing decayed, missing, and filled surfaces were significantly associated with stroke (adjusted HR, 1.006 [95% CI, 1.001-1.011]) and death (adjusted HR, 1.003 [95% CI, 1.001-1.005]) but not CHD (adjusted HR, 1.002 [95% CI, 1.000-1.005]). Regular dental care utilization lowered (adjusted odds ratio, 0.19 [95% CI, 0.16-0.22]; P<0.001) the chance of caries. CONCLUSIONS: Among the cohort, dental caries was independently associated with the risk of ischemic stroke and death, with the effect higher in African American participants. Regular dental care utilization was associated with a lower chance of caries, emphasizing its relevance in the prevention of these events.

Auditory-Perceptual Assessments of Cough: Characterizing Rater Reliability and the Effects of a Standardized Training Protocol.

INTRODUCTION: Auditory-perceptual assessments of cough are commonly used by speech-language pathologists working with people with swallowing disorders with emerging evidence beginning to demonstrate their validity; however, their reliability among novice clinicians is unknown. Therefore, the primary aim of this study was to characterize the reliability of auditory-perceptual assessments of cough among a group of novice clinicians. As a secondary aim, we assessed the effects of a standardized training protocol on the reliability of auditory-perceptual assessments of cough. METHODS: Twelve novice clinicians blindly rated ten auditory-perceptual cough descriptors for 120 cough audio clips. Standardized training was then completed by the group of clinicians. The same cough audio clips were then re-randomized and blindly rated. Reliability was analyzed pre- and post-training within each clinician (intra-rater), between each unique pair of raters (dyad-level inter-rater), and for the entire group of raters (group-level inter-rater) using intraclass correlation coefficients and Cohen's Kappa. RESULTS: Pre-training reliability was greatest for measures of strength, effectiveness, and normality and lowest when judging the type of expiratory maneuver (cough, throat clear, huff, other). The measures that improved the most with training were ratings of perceived crispness, amount of voicing, and type of expiratory maneuver. Intra-rater reliability coefficients ranged from 0.580 to 0.903 pre-training and 0.756-0.904 post-training. Dyad-level inter-rater reliability coefficients ranged from 0.295 to 0.745 pre-training and 0.450-0.804 post-training. Group-level inter-rater reliability coefficients ranged from 0.454 to 0.919 pre-training and 0.558-0.948 post-training. CONCLUSION: Reliability of auditory-perceptual assessments varied across perceptual cough descriptors, but all appeared within the range of what has been historically reported for auditory-perceptual assessments of voice and visual-perceptual assessments of swallowing and cough airflow. Reliability improved for most cough descriptors following 30-60 min of standardized training. Future research is needed to examine the validity of auditory-perceptual assessments of cough by assessing the relationship between perceptual cough descriptors and instrumental measures of cough effectiveness to better understand the role of perceptual assessments in clinical practice.

Characterizing the Validity of Using VASES to Derive DIGEST-FEES Grades.

INTRODUCTION: Visual Analysis of Swallowing Efficiency and Safety (VASES) and Dynamic Imaging Grade of Swallowing Toxicity for Flexible Endoscopic Evaluation of Swallowing (DIGEST-FEES) are two complimentary methods for assessing swallowing during FEES. Whereas VASES is intended to facilitate trial-level ratings of pharyngeal residue, penetration, and aspiration, DIGEST-FEES is intended to facilitate protocol-level impairment grades of swallowing safety and efficiency. The aim of this study was to assess the validity of using VASES to derive DIGEST-FEES impairment grades. METHODS: DIGEST-FEES grades were blindly analyzed from 50 FEES - first using the original DIGEST-FEES grading method (n = 50) and then again using a VASES-derived DIGEST-FEES grading method (n = 50). Weighted Kappa (κw) and absolute agreement (%) were used to assess the relationship between the original DIGEST-FEES grades and VASES-derived DIGEST-FEES grades. Spearman's correlations assessed the relationship between VASES-derived DIGEST-FEES grades with measures of construct validity. RESULTS: Substantial agreement (κw = 0.76-0.83) was observed between the original and VASES-derived grading methods, with 60-62% of all DIGEST-FEES grades matching exactly, and 92-100% of DIGEST-FEES grades within one grade of each other. Furthermore, the strength of the relationships between VASES-derived DIGEST-FEES grades and measures of construct validity (r = 0.34-0.78) were similar to the strength of the relationships between original DIGEST-FEES grades and the same measures of construct validity (r = 0.34-0.83). CONCLUSION: Findings from this study demonstrate substantial agreement between original and VASES-derived DIGEST-FEES grades. Using VASES to derive DIGEST-FEES also appears to maintain the same level of construct validity established with the original DIGEST-FEES. Therefore, clinicians and researchers may consider using VASES to increase the transparency and standardization of DIGEST-FEES ratings. Future research should seek to replicate these findings and explore the simultaneous use of VASES and DIGEST-FEES in a greater sampling of raters and across other patient populations.

Periodontal Disease Treatment After Stroke or Transient Ischemic Attack: The PREMIERS Study, a Randomized Clinical Trial.

BACKGROUND: Patients with stroke/transient ischemic attack and periodontal disease (PD) are at increased risk for cardiovascular events. PD treatments that can improve stroke risk factors were tested if they might assist patients with cerebrovascular disease. METHODS: In this multicenter phase II trial, patients with stroke/transient ischemic attack and moderately severe PD were randomly assigned to intensive or standard PD treatment arms. The primary outcome measure was a composite of death, myocardial infarction, and recurrent stroke, as well as adverse events. Secondary outcome included changes in stroke risk factors. RESULTS: A total of 1209 patients with stroke/transient ischemic attack were screened, of whom 481 met the PD eligibility criteria; 280 patients were randomized to intensive arm (n=140) and standard arm (n=140). In 12-month period, primary outcome occurred in 11 (8%) in the intensive arm and 17 (12%) in the standard arm. The intensive arm was nonsuperior to the standard arm (hazard ratio, 0.65 [95% CI, 0.30-1.38]) with similar rates of adverse events (sepsis 2.1% versus 0.7%; dental bleeding 1.4% versus 0%; and infective endocarditis 0.7% versus 0%). Secondary-outcome improvements were noted in both arms with diastolic blood pressure and high-density lipoprotein cholesterol (P<0.05). CONCLUSIONS: In patients with recent stroke/transient ischemic attack and PD, intensive PD treatment was not superior to standard PD treatment in prevention of stroke/myocardial infarction/death. Fewer events were noted in the intensive arm and the 2 arms were comparable in the safety outcomes. Secondary-outcome measures showed a trend toward improvement, with significant changes noted in diastolic blood pressure and high-density lipoprotein in both the treatment arms.

Rehabilitating Cough Dysfunction in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Disorders of airway protection (cough and swallowing) are pervasive in Parkinson's disease (PD) resulting in a high incidence of aspiration pneumonia and death. However, there are no randomized controlled trials comparing strength and skill-based approaches to improve airway protection in PD. OBJECTIVES: The aim of this study was to compare expiratory muscle strength training (EMST) and sensorimotor training for airway protection (smTAP) to improve cough-related outcomes in people with PD. METHODS: Participants with PD and dysphagia were recruited for this prospective phase II randomized-blinded controlled clinical trial. Participants completed baseline assessment, 5 weeks of EMST or smTAP, and a post-training assessment. Primary outcome measures included maximum expiratory pressure (MEP) and voluntary cough peak expiratory flow rate (PEFR). Mixed effects models were used to assess the effects of EMST and smTAP on outcomes. RESULTS: A total of 65 participants received either EMST (n = 34) or smTAP (n = 31). MEP improved from pre- to post-treatment for smTAP (P < 0.001, d = 0.19) and EMST (P < 0.001, d = 0.53). Voluntary PEFR increased from pre- to post-treatment for smTAP (P < 0.001, d = 0.19) and EMST (P < 0.001, d = 0.06). Moreover, reflex cough PEFR (P < 0.001, d = 0.64), reflex cough expired volume (P < 0.001, d = 0.74), and urge to cough (P = 0.018, OR = 2.70) improved for the smTAP group but not for the EMST group. CONCLUSIONS: This clinical trial confirmed the efficacy of smTAP to improve reflex and voluntary cough function, above and beyond EMST, the current gold standard. © 2022 International Parkinson and Movement Disorder Society.

The Role of Aspiration Amount on Airway Protective Responses in People with Neurogenic Dysphagia.

The aim of this study was to examine relationships between the presence vs. absence of an aspiration-related airway protective response (i.e., coughing or throat clearing) with aspiration amount, trial volume, disease diagnosis, and disease duration in people with neurologic disease. A secondary analysis was completed of flexible endoscopic evaluations of swallowing (FEES) in people with neurologic disease. Thin liquid boluses with endoscopically confirmed aspiration were included. Aspiration amount was measured for each trial using the visual analysis of swallowing efficiency and safety (VASES). Statistical analyses were used to (1) compare aspiration amount between swallows with vs. without an airway protective response and (2) examine if trial volume, disease duration, and disease diagnosis were related to the presence of airway protective responses when controlling for aspiration amount. 422 aspirated swallows across 86 FEES were analyzed. Of the 59 people who aspirated more than once, 66.1% exhibited variability in the presence vs. absence of an airway protective response. Statistical analyses revealed airway protective responses were significantly related to aspiration amount (p < 0.001; Marginal R2 = 0.46) and disease duration (p = 0.036, L.R. = 4.35) but not trial volume (p = 0.428) or disease diagnosis (p = 0.103). The participants in this study were less likely to cough or throat clear when having smaller amounts of aspiration or longer disease durations. Future research is needed to examine if aspiration amount is related to airway protective responses in healthy adults and across other patient populations.

Quantifying Impairments in Swallowing Safety and Efficiency in Progressive Supranuclear Palsy and Parkinson's Disease.

Dysphagia is a largely inevitable symptom in both progressive supranuclear palsy (PSP) and Parkinson's disease (PD). To date, comparative studies in these diseases have failed to detect differences in the severity of impairments in swallowing safety or efficiency, potentially due to small sample sizes and outcome measures with low sensitivity. Therefore, this study sought to address these limitations by using novel measurement methodology to comprehensively compare swallowing safety and efficiency impairments between these populations in order to better understand whether differences may exist and guide clinical management. Twenty-four participants with PSP and 24 with PD were matched for disease duration and completed flexible endoscopic evaluations of swallowing. A visual analog scale and penetration-aspiration scale quantified swallowing safety and efficiency. Bayesian multilevel models compared the frequency, severity, and variability of swallowing impairments. Individuals with PSP demonstrated greater impairments in swallowing safety, including deeper and more variable airway invasion and more frequent vocal fold and subglottic residue. Swallowing efficiency was also more impaired among individuals with PSP, including more frequent hypopharyngeal residue (with solids) and more severe residue in the oropharynx (with thin liquids and solids) and hypopharynx (with thin liquids). When airway or pharyngeal residue was present, similar within-subject variability of the amount of residue was appreciated across anatomic landmarks. This is the first study comparing the frequency, severity, and variability of swallowing impairments between PSP and PD populations. Our findings demonstrate more pronounced impairments in swallowing safety and efficiency for PSP compared to PD. These findings provide a clinically relevant characterization of swallowing measures using novel methodological and statistical approaches attempting to resolve some limitations of prior studies.

The Relationship Between Lingual Strength and Functional Swallowing Outcomes in Parkinson's Disease.

The purpose of this retrospective study was to determine whether reduced lingual strength was associated with functional swallowing outcomes in individuals with Parkinson's disease (PD). Participants (N = 42) completed evaluations of maximal lingual isometric pressure (MIP) and mean lingual swallowing pressure (MSP), and flexible endoscopic evaluations of swallowing. Regression models were used to determine the association between lingual strength and functional swallowing outcomes of airway invasion, the presence of post-swallow pharyngeal residue, and the amount of pharyngeal residue (when present). Results revealed that higher MIP (p = 0.002, OR 0.93) and higher MSP (p = 0.001 OR 0.88) were associated with less airway invasion of thin liquids. Both MIP and MSP were able to differentiate between those with and without dysphagia (MIP: AUC 0.7935, p = 0.001; MSP: AUC 0.75, p = 0.026). Neither MIP nor MSP was related to the presence of residue. However, when thin liquid oropharyngeal residue was present, both MIP (p < 0.001, OR 0.99) and MSP (p < 0.001; OR 0.98) were significantly associated with the amount of residue observed. Similarly, when thin liquid hypopharyngeal residue was present, MIP (p < 0.001, OR 0.99) and MSP (p < 0.001, OR 0.98) were associated with the amount of residue observed. These findings suggest a relationship between reduced lingual strength and worse thin liquid swallowing safety and efficiency; however, the magnitude of these effects was small. This indicates that lingual strength is one important contributing factor to functional swallowing impairments in PD and may identify those with unsafe swallowing. These findings have important clinical implications for including lingual strength in the screening, assessment, and management of dysphagia in PD.

Immediate Effects of Sensorimotor Training in Airway Protection (smTAP) on Cough Outcomes in Progressive Supranuclear Palsy: A Feasibility Study.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by a high prevalence of dysphagia, cough dysfunction, and resultant aspiration pneumonia. Sensorimotor cough function is important for airway clearance in people with dysphagia. Upregulation of cough has been demonstrated in healthy adults and Parkinson's disease; however, the feasibility of cough rehabilitation in PSP is unknown. We sought to assess feasibility by examining the immediate effects of a novel sensorimotor training in airway protection (smTAP) on upregulation of cough function in PSP. Fifteen individuals with PSP enrolled in this study. Baseline voluntary and reflex cough testing were completed. During smTAP, participants were presented with subthreshold capsaicin and instructed to cough with sufficient intensity to hit a target line (set 25% above baseline reflex peak cough flow) via cough airflow visual biofeedback. Twenty-five repetitions were targeted within a single session. Wilcoxon signed-rank tests compared cough airflow measures between baseline voluntary cough testing, the initial five trials of smTAP, and final five trials. Mean peak expiratory flow rate (PEFR) significantly increased from initial to final smTAP trials (p < 0.001). Fourteen participants increased PEFR, with gains of more than 10% in 11 participants. Variability of PEFR (p = 0.01) and cough expired volume (p = 0.01) significantly decreased across smTAP trials. This study is the first to demonstrate the ability of people with PSP to immediately upregulate cough function, providing preliminary support for the feasibility of cough rehabilitation in this population with this novel treatment approach. Future research examining the effects of multiple sessions of smTAP on cough outcomes is warranted.

Visual Analysis of Swallowing Efficiency and Safety (VASES): A Standardized Approach to Rating Pharyngeal Residue, Penetration, and Aspiration During FEES.

The primary aim of this study was to describe the development of the Visual Analysis of Swallowing Efficiency and Safety (VASES)-a standardized method to rate pharyngeal residue, penetration, and aspiration during FEES. As a secondary aim, we explored the feasibility of training novices to interpret FEES using VASES. Literature review and consensus panel discussions were used to develop standardized rules for VASES. A training protocol was developed and criterion ratings were established. Twenty-five novice raters completed VASES training and pre-/post-training assessments. Statistical analyses were used to examine pre- to post-training differences in the accuracy, reliability, and time to rate each video clip using VASES. Four sets of VASES rules were developed, including 'what', 'where', 'when', and 'how' to rate FEES. Large, significant post-training improvements in rating accuracy were observed across all seven VASES outcome measures (Cohen's d range 0.74-1.59). Additionally, inter-rater reliability increased for four of the seven outcome measures, and the amount of time to rate each video clip decreased from 2.6 min pre-training to 1.5 min post-training. VASES is a standardized FEES rating method used to enhance the subjective analysis of pharyngeal residue, penetration, and aspiration. It can be feasibly taught to novice raters with a high level of success and may be an effective method to analyze swallowing safety and efficiency in clinical and research practices. Future research is needed to test the validity of VASES by examining its relationship with other validated FEES rating scales.

Sensorimotor Cough Dysfunction Is Prevalent and Pervasive in Progressive Supranuclear Palsy.

BACKGROUND: Pneumonia, a leading cause of death in progressive supranuclear palsy (PSP), results from progressive and pervasive deficits of airway protection, including both cough and swallowing dysfunction. Cough protects the airway by expelling aspirate and may be an important therapeutic target to protect against pneumonia in the presence of dysphagia. However, cough has not been objectively characterized in PSP or compared to other common forms of parkinsonism, such as Parkinson's disease (PD). OBJECTIVE: The purpose of this study was to examine voluntary and reflex cough function in PSP, as compared to patients with PD matched for disease duration. METHODS: Twenty-six patients with PSP and 26 with PD completed voluntary and reflex cough testing via spirometry. Linear mixed effects models examined comparisons between groups and within cough types across cough sensory and motor outcomes. RESULTS: Patients with PSP demonstrated significantly reduced cough motor function compared to PD, specifically reduced peak expiratory flow rate (P < 0.001), cough expiratory volume (P < 0.001), and cough inspiratory volume (P = 0.008). Both groups showed similar reflex cough thresholds (P = 0.694), but PSP demonstrated an increased perception of cough stimuli (P = 0.041). CONCLUSIONS: These findings suggest that sensorimotor cough dysfunction is prevalent in PSP, and cough motor deficits, in particular, are worse in PSP than in PD. These deficits likely contribute to the pathogenesis of pneumonia in PSP. Therefore, cough should be integrated into assessments of airway protection and considered as a therapeutic target to potentially reduce adverse health events and improve quality of life in this population. © 2021 International Parkinson and Movement Disorder Society.

Detection of Aspiration, Penetration, and Pharyngeal Residue During Flexible Endoscopic Evaluation of Swallowing (FEES): Comparing the Effects of Color, Coating, and Opacity.

The aim of this study was to assess the effects of color, coating, and opacity on the detection of aspiration, penetration, and residue during flexible endoscopic evaluations of swallowing (FEES). Thirty dysphagic adults underwent FEES while swallowing five 5 mL thin liquid boluses (1 × each, randomized): white water, blue water, white milk, blue milk, and barium water. To assess the effects of color, blue milk was compared to white milk. To assess the effects of coating, barium, white water, and white milk were compared to each other. To assess the effects of opacity, blue milk was compared to blue water. Videos were blindly analyzed and judged for the presence of pharyngeal residue, penetration, and aspiration. Repeated measures analyses were used to assess differences in the frequency of detection across bolus types. Pharyngeal residue was detected more frequently for liquids that were blue, had a coating effect, or were opaque (p < 0.05) when compared to liquids that were white, did not have a coating effect, or were translucent, respectively. Penetration and aspiration were detected more frequently for liquids that had a coating effect (p < 0.05), but not for liquids that were colored blue or opaque (p > 0.05). Coating appears to be the most important factor detecting thin liquid residue, penetration, and aspiration during FEES. Given these findings, standardized use of boluses that possess a coating effect (e.g., white-dyed water or barium) is highly recommended to enhance the sensitivity of identifying impairments in swallowing safety and efficiency during FEES.

Effects of Verbal Cueing on Respiratory-Swallow Patterning, Lung Volume Initiation, and Swallow Apnea Duration in Parkinson's Disease.

Respiratory-swallow coordination (RSC) is important for swallowing safety. Atypical RSC is common in Parkinson's disease (PD) and is associated with the presence of dysphagia and aspiration. Verbal cueing is known to affect RSC in healthy adults, yet an understanding of its effect on RSC in PD is unknown. Therefore, the aims of this study were to: (1) assess the effects of verbal cueing on respiratory-swallow patterning, lung volume initiation, and swallow apnea duration in PD; and (2) determine when during tidal breathing verbal cues should be given in order to increase the likelihood of eliciting optimal RSC. People with PD were prospectively recruited for respiratory-swallowing assessments during cued and non-cued swallowing conditions. Non-cued trials consisted of swallowing in an unprompted fashion, while cued trials consisted of swallowing only once participants were verbally instructed. Verbal cues were given at four specific points during tidal breathing. Nonparametric tests were used to compare differences in patterning, lung volume, and swallow apnea duration between the cued and non-cued swallows. Twenty-five people with PD were enrolled, yielding an analysis of 375 swallows. Verbal cueing significantly affected respiratory-swallow patterning (p < 0.0005), lung volume initiation (p < 0.0005), and swallow apnea duration (p < 0.0005). The effects of verbal cueing on RSC differed significantly depending on when during tidal breathing verbal cues were given. Cues given at high tidal inhalation were most likely to elicit optimal RSC, while cues given at low tidal exhalation were the least likely to elicit optimal RSC. The results of this study demonstrate that verbal cueing significantly affects RSC in PD. Depending on when verbal cues are given during tidal breathing, RSC can become more safe and coordinated or more atypical and risky. Clinicians should be cognizant of these effects by avoiding verbal cues if attempting to evaluate normal RSC during swallowing evaluations and cueing for swallows at the time of high tidal inhalation when targeting more optimal RSC in PD.

Handheld Cough Testing: A Novel Tool for Cough Assessment and Dysphagia Screening.

Aspiration pneumonia is a leading cause of death in Parkinson's disease (PD), occurring as a result of impaired cough and swallowing function. However, portable diagnostic tools for cough assessment and dysphagia screening are limited. Therefore, the aims of this study were to determine if: (1) 'Handheld Cough Testing' (HCT), a novel tool developed for cough assessments, could detect differences in cough airflow and sensation during reflex and voluntary cough tasks; and (2) HCT could screen for dysphagia in PD with high sensitivity. Twenty-two people with PD underwent HCT and swallowing assessments. Cough airflow ('PEFR') and sensation ('UTC') was recorded during reflex and voluntary cough tasks. Flexible endoscopy was used to identify people with and without dysphagia. Within-subject statistical analyses were used to detect differences in PEFR and UTC across cough tasks and between-subject statistical analyses were used to detect differences in cough function between people with and without dysphagia. Results revealed significant differences in PEFR (p < 0.0005) and UTC (p < 0.0005) across cough tasks using HCT. Additionally, reflex cough PEFR was significantly different between people with and without dysphagia (p < 0.05). A cut-off of 42.5 L/min exhibited an excellent ability to predict dysphagia in people with PD (90.9% sensitivity; 80.0% specificity). This study revealed that HCT was a valid tool for cough assessment and dysphagia screening. It identified differences in cough airflow and sensation during reflex and voluntary cough tasks and screened for people with dysphagia in PD with high sensitivity.

Predictors of Residue and Airway Invasion in Parkinson's Disease.

Dysphagia is a highly prevalent disorder in Parkinson's Disease (PD) characterized by changes in swallowing kinematics, residue, and airway invasion. These changes can lead to serious medical morbidities including malnutrition, aspiration pneumonia, and death. However, little is known about the most predictive causes of residue and airway invasion in this patient population. Therefore, the aims of this study were to (1) assess how disease severity affects residue, airway invasion, and swallowing kinematics in PD; and (2) determine which swallowing kinematic variables were most predictive of residue and airway invasion. A secondary analysis of forty videofluoroscopic swallow studies (VFSS) from individuals with early through mid-stage PD was performed. Airway invasion (Penetration-Aspiration Scale 'PAS'), residue (Bolus Clearance Ratio 'BCR'), and ten spatiotemporal swallowing kinematic variables were analyzed. Statistical analyses were used to determine if disease severity predicted residue, depth of airway invasion, and swallowing kinematics, and to examine which swallowing kinematic variables were most predictive of residue and the presence of airway invasion. Results revealed that residue and the presence of airway invasion were significantly predicted by swallowing kinematics. Specifically, airway invasion was primarily influenced by the extent and timing of airway closure, while residue was primarily influenced by pharyngeal constriction. However, disease severity did not significantly predict changes to swallowing kinematics, extent of residue, or depth of airway invasion during VFSS assessment. This study comprehensively examined the pathophysiology underlying dysphagia in people with early to mid-stage PD. The results of the present study indicate that disease severity alone does not predict swallowing changes in PD, and therefore may not be the best factor to identify risk for dysphagia in PD. However, the swallowing kinematics most predictive of residue and the presence of airway invasion were identified. These findings may help to guide the selection of more effective therapy approaches for improving swallowing safety and efficiency in people with early to mid-stage PD.

Pharyngeal Area Changes in Parkinson's Disease and Its Effect on Swallowing Safety, Efficiency, and Kinematics.

Pharyngeal area can increase as a function of normal healthy aging and muscle atrophy. These increases in pharyngeal area can negatively affect swallowing function in healthy older adults (HOA). However, the presence of pharyngeal area changes and their effects on swallowing function in Parkinson's disease (PD) remain unknown. Therefore, we compared the pharyngeal area of people with PD to HOA to determine if pharyngeal area changes were present in PD above and beyond what is seen in HOA. Within PD, we also evaluated if and how an increase in pharyngeal area affects swallowing kinematics, swallowing safety, and swallowing efficiency. A secondary analysis of videofluoroscopic swallow studies was completed comparing 41 HOA and 40 people with PD. Measures of pharyngeal area, swallowing kinematics, swallowing safety (penetration/aspiration), and swallowing efficiency (residue) were analyzed. An analysis of covariance (ANCOVA) was used to determine if pharyngeal area was significantly different between the HOA and PD groups while controlling for age, sex, and height. Regression analyses were used to examine if and how pharyngeal area influenced swallowing kinematics, swallowing safety, and swallowing efficiency in PD. Pharyngeal areas were significantly larger for people with PD when compared to HOA (p = .008). An increase in pharyngeal area was associated with less pharyngeal constriction (p = .022), shorter duration of airway closure (p = .017), worse swallowing safety (p < .0005), and worse swallowing efficiency (p = .037). This study revealed that pharyngeal areas are larger in people with PD when compared to HOA, and that this increase in pharyngeal area is associated with maladaptive changes to swallowing kinematics, residue, and penetration/aspiration. These findings support the notion that pharyngeal muscle atrophy may be exacerbated in PD above and beyond what is seen in normal, healthy aging group. Results from this study highlight the need to consider pharyngeal muscle atrophy as a source for swallowing dysfunction in PD, and as a potential treatment target for swallowing rehabilitation.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy.

BACKGROUND: CCAAT enhancer-binding protein epsilon (C/EBPε) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBPε is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. OBJECTIVE: The aim of this study was to molecularly characterize the effects of C/EBPε transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. METHODS: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. RESULTS: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. CONCLUSION: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBPε. Mutated C/EBPε acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBPε. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

Novel IL2RG Mutation Causes Leaky TLOWB+NK+ SCID With Nodular Regenerative Hyperplasia and Normal IL-15 STAT5 Phosphorylation.

X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.

Superior and Anterior Hyoid Displacement During Swallowing in Non-Dysphagic Individuals.

The Dynamic Swallow Study (DSS) is a methodology used to objectively and quantitatively assess swallowing kinematics during Videofluoroscopic Swallow Studies (VFSS). No DSS normative data exist delineating superior and anterior hyoid displacement (Hsup and Hant, respectively), nor the ratio between Hsup and Hant (SAratio). The aims of this study were to (1) establish normative data for Hsup, Hant, and SAratio and (2) assess the effects of age, sex, and bolus size on these measures in non-dysphagic patients, within the context of DSS. VFSSs were reviewed for consecutive elderly (≥ 65 years) and non-elderly (< 65 years) male and female non-dysphagic patients. Measurements of Hsup, Hant, and SAratio were made using a novel measurement methodology within the context of the Dynamic Swallow Study (DSS) protocol. Statistical analysis was performed to establish interaction effects and main effects of age, sex, and bolus size on Hsup, Hant, and SAratio. Descriptive statistics (mean ± standard deviations) are outlined for Hsup, Hant, and SAratio. Hsup was significantly effected by bolus size and age. Additionally, a significant three-way interaction of age, sex, and bolus size was observed. Hant was significantly effected by bolus size and sex, but no two- or three-way interactions were present. Neither bolus size, age, nor sex significantly effected SAratio. Age, sex, and bolus size normative data were established for Hsup, Hant, and SAratio for VFSS kinematic analysis. By outlining these measures, one can more thoroughly evaluate the areas of specific swallowing impairment, better determine the therapy targets, and track changes over time.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.